[Treatment of haemophilia in Austria]. / Hämophilie-Behandlung in Österreich.

This guideline is intended to provide practical guidance for the diagnosis and treatment of haemophilia in Austria. Few randomized controlled interventional trials are available addressing the treatment of haemophilia, therefore recommendations are usually based on low level of evidence and represent expert consensus.This guideline is based on the WFH guideline, published in 2020, and adapted according to the national circumstances and experience.It includes recommendations and suggestions for diagnosis and follow-up visits and pharmacological therapies for treatment and prophylaxis. Further topics comprise special aspects in children and adults with severe haemophilia, outcome measurement, and management of trauma, special bleedings and interventions, including dental procedures, inhibitors, management of haemophilia carriers, and psychosocial aspects.

Metal leakage from orthodontic appliances chemically alters enamel surface during experimental in vitro simulated treatment.

Human enamel is composed mainly of apatite. This mineral of sorption properties is susceptible to chemical changes, which in turn affect its resistance to dissolution. This study aimed to investigate whether metal leakage from orthodontic appliances chemically alters the enamel surface during an in vitro simulated orthodontic treatment. Totally 107 human enamel samples were subjected to the simulation involving metal appliances and cyclic pH fluctuations over a period of 12 months in four complimentary experiments. The average concentrations and distribution of Fe, Cr, Ni, Ti and Cu within the enamel before and after the experiments were examined using ICP‒MS and LA‒ICP‒MS techniques. The samples exposed to the interaction with metal appliances exhibited a significant increase in average Fe, Cr and Ni (Kruskal-Wallis, p < 0.002) content in comparison to the control group. The outer layer, narrow fissures and points of contact with the metal components showed increased concentrations of Fe, Ti, Ni and Cr after simulated treatment, conversely to the enamel sealed with an adhesive system. It has been concluded that metal leakage from orthodontic appliances chemically alters enamel surface and microlesions during experimental in vitro simulated treatment.

Immunogenicity and safety of COVID-19 booster vaccination: A population-based clinical trial to identify the best vaccination strategy.

BACKGROUND: Various SARS-CoV-2 variants of concerns (VOCs) characterized by higher transmissibility and immune evasion have emerged. Despite reduced vaccine efficacy against VOCs, currently available vaccines provide protection. Population-based evidence on the humoral immune response after booster vaccination is crucial to guide future vaccination strategies and in preparation for imminent COVID-19 waves. METHODS: This multicenter, population-based cohort study included 4697 individuals ≥18 years of age who received a booster vaccination. Antibody levels against SARS-CoV-2 receptor binding domain (RBD) and neutralizing antibodies against wild-type (WT) virus and Omicron variants were assessed at baseline (day of booster vaccination) and after four weeks. Safety was evaluated daily within the first week using a participant-completed electronic diary. Antibody levels were compared across different vaccination strategies, taking into account individual host factors. RESULTS: Our main model including 3838 participants revealed that individuals who received a booster with mRNA-1273 compared to BNT162b2 vaccine had a significantly higher increase (95 %CI) in anti-RBD-antibody levels (37,707 BAU/mL [34,575-40,839] vs. 27,176 BAU/mL [26,265-28,087]), and of neutralization levels against WT (1,681 [1490-1872] vs. 1141 [1004-1278] and Omicron variant (422 [369-474] vs. 329 [284-374]). Neutralizing antibody titres highly correlated with anti-RBD antibodies, with neutralizing capacity 4.4 fold higher against WT compared to Omicron. No differences in safety were found between the two booster vaccines. CONCLUSION: Our study underlines the superiority of a booster vaccination with mRNA-1273, independent of the primary vaccination and therefore provides guidance on the vaccination strategy.

Autoimmune and paraneoplastic seizures.

Seizures are a common feature of autoimmune encephalitis and are especially prevalent in patients with the commonest autoantibodies, against LGI1, CASPR2 and the NMDA, GABAB, and GABAA receptors. In this chapter, we discuss the classification, clinical, investigation, and treatment aspects of patients with these, and other autoantibody-mediated and -associated, illnesses. We highlight distinctive and common seizure semiologies which, often alongside other features we outline, can help the clinical diagnosis of an autoantibody-associated syndrome. Next, we classify these syndromes by either focusing on whether they represent underlying causative autoantibodies or T-cell-mediated syndromes and on the distinction between acute symptomatic seizures and a more enduring tendency to autoimmune-associated epilepsy, a practical and valuable distinction for both patients and clinicians which relates to the pathogenesis. We emphasize the more effective immunotherapy response in patients with causative autoantibodies, and discuss the emerging evidence for various first-, second-, and third-line immunotherapies. Finally, we highlight available clinical rating scales which can guide autoantibody testing and immunotherapy in patients with seizures of unknown etiology. Throughout, we relate the clinical and therapeutic observations to the immunobiology and neuroscience which drive these seizures.

Nanofiber Ion-Selective Membrane-Coated Carbon Paper All-Solid-State Sensors: One Stone, Two Birds.

Potentiometric sensors with nanostructural ion-selective membranes were prepared and tested. Electrospun nanofiber mats were applied in novel all-solid-state sensors, using carbon paper as an electronically conducting support. For the sake of simplicity, application of a solid contact layer was avoided, and redox-active impurities naturally present in the carbon paper have proven to be effective as ion-to-electron transducers. Application of a nanostructural ion-selective membrane requires an innovative approach to combine the receptor layer with the support. The nanofiber mat portion was fused with carbon paper in a hot-melt process. Applying temperature close to 120 °C for a short time (3 s) allowed binding the nanostructural ion-selective membrane with carbon paper, without significant changes in the nanofiber structure. This process was conveniently performed together with the lamination of the carbon paper support. The thus obtained, potentially disposable sensors were characterized as exhibiting highly reproducible potential readings in time as well as between sensors belonging to the same batch. The benefits of the application of nanostructural ion-selective membranes include shorter equilibration time, lower detection limit, and significantly lower material consumption. However, the nanostructural membrane is characterized by a higher electrical resistance, which is attributed to higher porosity.

Finding a perfect match of ion-exchanger and plasticizer for ion-selective sensors.

Application of neutral ionophore based ion-selective sensors requires presence of ion-exchanger in the receptor phase, silently assuming that it is not only soluble but also dissociates to ions in the applied plasticizer. Although for typically applied ion-selective membrane constituents (plasticizers - ion-exchanger pairs) dissociation of ion-exchangers to ions is proven by theoretical (or close to) performance of resulting sensors, search for alternative plasticizers or ion-exchangers requires a method allowing estimation of the match of properties of involved compounds. In this work we propose a simple optical approach allowing estimation of ion-exchanger interactions with plasticizer. The results were confirmed by conductivity studies of model plasticizers solutions. The estimated dissociation constants of model ion-exchangers in plasticizers used are in excellent agreement with the results of optical studies. It was shown that solubility coupled with poor dissociation to ions of ion-exchanger affects performance of the resulting ion-selective membrane. Rational choice of properties of ion-exchanger and plasticizer allows finding a perfect match of the two, that results in improvements in performance of sensors (e.g. detection limits). As model sensors potassium and sodium ion-selective electrodes with poly(vinyl chloride) (PVC) based membranes, plasticized with classical plasticizer bis(2-ethylhexyl sebacate) or biodegradable alternative acetyl tributyl citrate, were prepared and studied using selected ion-exchangers.

Counterion-controlled phase equilibria in a charge-regulated polymer solution.

We study phase equilibria in a minimal model of charge-regulated polymer solutions. Our model consists of a single polymer species whose charge state arises from protonation-deprotonation processes in the presence of a dissolved acid, whose anions serve as screening counterions. We explicitly account for variability in the polymers' charge states. Homogeneous equilibria in this model system are characterised by the total concentration of polymers, the concentration of counter-ions and the charge distributions of polymers which can be computed with the help of analytical approximations. We use these analytical results to characterise how parameter values and solution acidity influence equilibrium charge distributions and identify for which regimes uni-modal and multi-modal charge distributions arise. We then study the interplay between charge regulation, solution acidity and phase separation. We find that charge regulation has a significant impact on polymer solubility and allows for non-linear responses to the solution acidity: Re-entrant phase behaviour is possible in response to increasing solution acidity. Moreover, we show that phase separation can yield to the coexistence of local environments characterised by different charge distributions.

Resolving the spatial architecture of myeloma and its microenvironment at the single-cell level.

In multiple myeloma spatial differences in the subclonal architecture, molecular signatures and composition of the microenvironment remain poorly characterized. To address this shortcoming, we perform multi-region sequencing on paired random bone marrow and focal lesion samples from 17 newly diagnosed patients. Using single-cell RNA- and ATAC-seq we find a median of 6 tumor subclones per patient and unique subclones in focal lesions. Genetically identical subclones display different levels of spatial transcriptional plasticity, including nearly identical profiles and pronounced heterogeneity at different sites, which can include differential expression of immunotherapy targets, such as CD20 and CD38. Macrophages are significantly depleted in the microenvironment of focal lesions. We observe proportional changes in the T-cell repertoire but no site-specific expansion of T-cell clones in intramedullary lesions. In conclusion, our results demonstrate the relevance of considering spatial heterogeneity in multiple myeloma with potential implications for models of cell-cell interactions and disease progression.

Elemental imaging approach to comparative analysis of historical inks. Proof of concept based on non-invasive examinations of the Chopin manuscript as a case study.

This work presents an indirect method of investigating the elemental diversity of historical inks. The manuscript of Fryderyk Chopin's Impromptu in A flat major, Op. 29 was examined as an example of the proposed approach for testing documents containing different inks. Preliminary in situ X-ray fluorescence (XRF) measurements carried out it the museum storage room provided qualitative reference data for the object. Then, selected areas on the item were examined with indicator papers soaked in 4,7-diphenyl-1,10-phenanthroline (Bphen). The reaction with the ligand enabled the immediate colorimetric detection of Fe(II) in the form of magenta Fe(Bphen)3 complex. The overall condition of the manuscript with regard to the risk of ink corrosion was assessed in this way. More chemical information were obtained by the proposed elemental imaging-based approach to evaluate chemical heterogeneity of the used indicator paper samples using laser ablation inductively coupled plasma mass spectrometry (LA-ICP-MS). The recorded data were visualised in the form of elemental distribution maps. The Fe enriched areas indicated Regions of Interest (ROIs) to approximate composition of the inks from the manuscript. All calculations were done solely for the data mathematically singled out from these areas. The varying proportions of AI, Mn, Co and Cu relative to Fe correlated with the ROIs of the composer's handwriting, editor's notes and stave lines, demonstrating the applicability of the proposed approach for comparative studies.

Application of Monoferrocenylsumanenes Derived from Sonogashira Cross-Coupling or Click Chemistry Reactions in Highly Sensitive and Selective Cesium Cation Electrochemical Sensors.

This paper reports the synthesis and characterization of novel monoferrocenylsumanenes obtained by means of the Sonogashira cross-coupling or click chemistry reaction as well as their application in cesium cation electrochemical sensors. A new synthetic protocol based on Sonogashira cross-coupling was developed for the synthesis of monoferrocenylsumanene or ethynylsumanene. The click chemistry reaction was introduced to the sumanene chemistry through the synthesis of 1,2,3-triazole containing monoferrocenylsumanene. The designed synthetic methods for the modification of sumanene at the aromatic position proved to be efficient and proceeded under mild conditions. The synthesized sumanene derivatives were characterized by detailed spectroscopic analyses of the synthesized sumanene derivatives. The supramolecular interactions between cesium cations and the synthesized monoferrocenylsumanenes were spectroscopically and electrochemically investigated. Furthermore, the design of the highly selective and sensitive cesium cation fluorescence and electrochemical sensors comprising the synthesized monoferrocenylsumanenes as receptor compounds was analyzed. The tested cesium cation electrochemical sensors showed excellent limit of detection values in the range of 6.0-9.0 nM. In addition, the interactions between the synthesized monoferrocenylsumanenes and cesium cations were highly selective, which was confirmed by emission spectroscopy, laser ablation inductively coupled plasma mass spectrometry (LA-ICP-MS), and cyclic voltammetry.

Synthesis of π-extended and bowl-shaped sumanene-ferrocene conjugates and their application in highly selective and sensitive cesium cations electrochemical sensors.

Carbon-carbon bond formation, condensation or click chemistry reactions were used to synthesize novel bowl-shaped sumanene-ferrocene conjugates, along with the extended π-electron framework in good yields. For the first time, the present study uses sumanene derivatives tris-substituted at the benzylic positions as the materials to begin the study on the click chemistry or the metal-catalyzed coupling reactions, Suzuki-Miyaura or Sonogashira couplings. The synthesized conjugates exhibited the property of selective recognizing cesium cations. As a result, this led to the development of highly sensitive and selective fluorescent or electrochemical sensors dedicated to the recognition of cesium cations (Cs+) in water. We successfully designed the Cs+ electrochemical sensors, which exhibited an acceptable limit of detection (LOD) values at 0.05-0.38 µM. Spectrofluorimetry, voltammetry, and laser ablation inductively coupled plasma mass spectrometry (LA-ICP-MS) were used to perform the selectivity studies. The results revealed that the designed sensors are highly Cs+-selective. This work significantly contributes to the design of new methods of sumanene modification. It also provides further information on the electrochemical properties and innovative applications of metallocene-tethered sumanene derivatives.

Reduced immunogenicity of BNT162b2 booster vaccination in combination with a tetravalent influenza vaccination: results of a prospective cohort study in 838 health workers.

OBJECTIVE: To investigate the immunogenicity and safety of BNT162b2 booster vaccination with and without a tetravalent influenza vaccine. METHODS: A prospective, open-label cohort study on immunogenicity and safety of COVID-19 booster vaccination with or without a tetravalent influenza vaccine was performed. Eight hundred thirty-eight health care workers were included in the following study arms: BNT162b2 booster-only, influenza-vaccine-only or combination of both. Levels of antibodies against SARS-CoV-2 spike receptor binding domain, and haemagglutinin inhibition tested for four different influenza strains (A(H1N1)pdm09, A(H3N2), B/Victoria, B/Yamagata) were measured at the time of vaccination and 4 weeks later. RESULTS: After 4 weeks, median (interquartile range) levels of antibodies against the receptor binding domain of the viral spike (S) protein and relative change from baseline were high in individuals who received BNTb162b2 booster vaccination only (absolute: 16 600 [10 980-24 360] vs. 12 630 [8198-18 750] BAU/mL [p < 0.0001]; relative increase: 49% [23.6-95.3] vs. 40% [21.9-80.6] [p 0.048]; booster-only n = 521 vs. combination-arm n = 229 respectively). Results were confirmed after matching for sex, age, body mass index, baseline antibody levels and vaccine compound received for primary immunization (absolute: 13 930 [10 610-22 760] vs. 12 520 [8710-17 940]; [p 0.031]; relative increase: 55.7% [27.8-98.5] vs. 42.2% [22.9-74.5]; p 0.045). Adverse events were almost identical in the booster-only and the combination-arm, but numerically low in the influenza arm (525/536 [97.9%] vs. 235/240 [97.9%] vs. 26/33 [78.8 %]). DISCUSSION: Although no safety concerns occurred, our study provides evidence on reduced immunogenicity of a BNT162b2 booster vaccination in combination with a tetravalent influenza vaccine. Further studies investigating new influenza variants as well as potential differences vaccine effectiveness are needed.

Multiparametric Prediction Models for Coronavirus Disease 2019 Vaccine Selection: Results of a Comparative Population-Based Cohort Study.

BACKGROUND: An understanding vaccine-dependent effects on protective and sustained humoral immune response is crucial to planning future vaccination strategies against coronavirus disease 2019 (COVID-19). METHODS: In this multicenter, population-based, cohort study including 4601 individuals after primary vaccination against COVID-19 ≥ 4 months earlier we compared factors associated with residual antibody levels against severe acute respiratory syndrome coronavirus-2 receptor-binding domain (RBD) across different vaccination strategies (BNT162b2, mRNA-1273, or ChAdOx1). RESULTS: Our main model including 3787 individuals (2 × BNT162b2, n = 2271; 2 × mRNA-1273, n = 251; 2 × ChAdOx1, n = 1265), predicted significantly lower levels of anti-RBD antibodies after 6 months in individuals vaccinated with ChAdOx1 (392.7 binding antibody units per milliliter [BAU/mL]) compared with those vaccinated with BNT162b2 (1179.5 BAU/mL) or mRNA-1273 (2098.2 BAU/mL). Vaccine-dependent association of antibody levels was found for age with a significant predicted difference in BAU/ml per year for BNT162b2 (-21.5; 95% confidence interval [CI], -24.7 to -18.3) and no significant association for mRNA-1273 (-4.0; 95% CI, -20.0 to 12.1) or ChAdOx1 (1.7; 95% CI, .2 to 3.1). The predicted decrease over time since full immunization was highest in mRNA-1273 (-23.4; 95% CI, -31.4 to -15.4) compared with BNT162b2 (-5.9; 95% CI, -7 to -4.8). CONCLUSIONS: Our study revealed population-based evidence of vaccine-dependent effects of age and time since full immunization on humoral immune response. Findings underline the importance of individualized vaccine selection, especially in elderly individuals.

Performance Score (T2D)-A New Perspective in the Assessment of Six-Minute Walking Tests in Pulmonary Rehabilitation.

Because absolute changes in outcomes are difficult to interpret and the minimal clinically important difference (MCID) is not suitable to address this challenge, a novel method of classifying outcomes by relating changes to baseline values is warranted. We used the "performance score" (T2D), which reflects individual performance, enabling us to consider the functional status at the beginning of rehabilitation without dealing with the problems of mathematical coupling or regression effects, as encountered in ANCOVA. To illustrate the T2D, we retrospectively analyzed changes in the six-minute walking test (6MWT) in COPD patients undergoing outpatient pulmonary rehabilitation and compared the results with absolute differences related to a predetermined MCID. We evaluated a total of 575 COPD patients with a mean age of 61.4 ± 9.2 years. 6MWT improved significantly, with a mean change of 32.3 ± 71.2. A total of 105/311 participants who had reached the MCID were still classified as "below average" by the T2D. Conversely, 76/264 patients who had not reached the MCID were classified as "above average". This new performance measure accounts for the patient's current status and for changes over time, potentially representing a simple and user-friendly tool that can be used to quantify a patient's performance and response to rehabilitation.

Effects of pulsed electromagnetic field therapy on outcomes associated with osteoarthritis : A systematic review of systematic reviews.

BACKGROUND: Osteoarthritis (OA) is a chronic degenerative disease of multiple joints with a rising prevalence. Pulsed electromagnetic field (PEMF) therapy may provide a cost-effective, noninvasive, and safe therapeutic modality with growing popularity and use in physical medicine and rehabilitation. The purpose of this study was to synthesize the current knowledge on the use of PEMF in OA. METHODS: A systematic review of systematic reviews was performed. The PubMed, Embase, PEDro and Web of Science databases were searched based on a predetermined protocol. RESULTS: Overall, 69 studies were identified. After removing the duplicates and then screening title, abstract and full text, 10 studies were included in the final analysis. All studies focused on knee OA, and four studies also reported on cervical, two on hand, and one on ankle OA. In terms of the level of evidence and bias, most studies were of low or medium quality. Most concurrence was observed for pain reduction, with other endpoints such as stiffness or physical function showing a greater variability in outcomes. CONCLUSION: The PEMF therapy appears to be effective in the short term to relieve pain and improve function in patients with OA. The existing studies used very heterogeneous treatment schemes, mostly with low sample sizes and suboptimal study designs, from which no sufficient proof of efficacy can be derived. A catalogue of measures to improve the quality of future studies has been drawn up.

Successful application of pulsed electromagnetic fields in a patient with post-COVID-19 fatigue: a case report.

BACKGROUND: Post-COVID-19 fatigue is a frequent symptom in COVID-19 survivors, which substantially limits patients to achieve full recovery and potentially restrains return to work. The previous literature has not yet reported the use of pulsed electromagnetic fields in this indication. METHODS: Over the course of 5 weeks, 10 sessions of pulsed electromagnetic field treatment with a high magnetic flux density were applied to a patient suffering from post-COVID-19 fatigue syndrome. Fatigue, work ability, quality of life as well as anxiety, depression, stress level, and resilience were evaluated using validated patient-reported outcome measures. RESULTS: Fatigue, work ability, quality of life, and psychological well-being improved clearly over the course of the treatment and showed stable results 6 weeks later. CONCLUSION: The use of pulsed electromagnetic field therapy with a device that allows sufficient penetration of the body tissue might be a promising physical modality to manage post-COVID-19 fatigue syndrome, which could reduce clinical and economic health consequences. Clinical sham-controlled studies are needed to evaluate the effect of pulsed electromagnetic fields in this indication.

The effect of biofeedback interventions on pain, overall symptoms, quality of life and physiological parameters in patients with pelvic pain : A systematic review.

BACKGROUND: Biofeedback is recognized as an effective additive method for treating certain phenotypes of chronic pelvic pain syndrome and is a therapeutic option in other pelvic pain conditions. This review aims to evaluate evidence from the literature with a focus on the effect of biofeedback on pain reduction, overall symptom relief, physiological parameters and quality of life. METHODS: A systematic literature search was conducted using the databases PubMed, MEDLINE, Embase, Cochrane Library and PEDro from inception to July 2020. Data were tabulated and a narrative synthesis was carried out, since data heterogeneity did not allow a meta-analysis. The PEDro scale and the McMaster Critical Review Form-Quantitative Studies were applied to assess risk of bias. RESULTS: Out of 651 studies, 37 quantitative studies of primary research evaluating pelvic pain conditions in male and female adults and children were included. They covered biofeedback interventions on anorectal disorders, chronic prostatitis, female chronic pelvic pain conditions, urologic phenotypes in children and adults and a single study on low back pain. For anorectal disorders, several landmark studies demonstrate the efficacy of biofeedback. For other subtypes of chronic pelvic pain conditions there is tentative evidence that biofeedback-assisted training has a positive effect on pain reduction, overall symptoms relief and quality of life. Certain factors have been identified that might be relevant in improving treatment success. CONCLUSIONS: For certain indications, biofeedback has been confirmed to be an effective treatment. For other phenotypes, promising findings should be further investigated in robust and well-designed randomized controlled trials.

Pain management in hemophilia: expert recommendations.

INTRODUCTION: As a typical consequence of bleeding into muscles and joints, patients with severe hemophilia suffer from acute and chronic pain. In spite of its high prevalence, pain in this patient group is not always sufficiently considered or treated in an effective manner. AIM: The recommendations presented in this paper address possible improvements in pain management in hemophilia patients and particularities that have to be taken into account in this patient group. METHOD: The manifold aspects of pain management in hemophilia patients were discussed within the framework of an expert meeting. Based on the available literature and the experts' clinical experience, the participants developed a set of recommendations presented in this paper. RESULTS: Pain management in patients with hemophilia is often insufficient, a fact that not only influences the patients' quality of life but also implies the risk of difficult to manage chronic pain. Both the prevalent polypharmacy (due to comorbidities) as well as the underlying disease itself present special challenges to pain therapy in this patient group. The present review and recommendations are intended to support medical professionals in recognising the risks of pain chronicity, applying basic principles of multimodal pain therapy, including the options of psychological intervention and modalities of physical medicine in therapy concepts, and reaching a comprehensive understanding of the range of analgesic options available.

Tracking of Glycans Structure and Metallomics Profiles in BRAF Mutated Melanoma Cells Treated with Vemurafenib.

Nearly half of patients with advanced and metastatic melanomas harbor a BRAF mutation. Vemurafenib (VEM), a BRAF inhibitor, is used to treat such patients, however, responses to VEM are very short-lived due to intrinsic, adaptive and/or acquired resistance. In this context, we present the action of the B-Raf serine-threonine protein kinase inhibitor (vemurafenib) on the glycans structure and metallomics profiles in melanoma cells without (MeWo) and with (G-361) BRAF mutations. The studies were performed using α1-acid glycoprotein (AGP), a well-known acute-phase protein, and concanavalin A (Con A), which served as the model receptor. The detection of changes in the structure of glycans can be successfully carried out based on the frequency shifts and the charge transfer resistance after interaction of AGP with Con A in different VEM treatments using QCM-D and EIS measurements. These changes were also proved based on the cell ultrastructure examined by TEM and SEM. The LA-ICP-MS studies provided details on the metallomics profile in melanoma cells treated with and without VEM. The studies evidence that vemurafenib modifies the glycans structures and metallomics profile in melanoma cells harboring BRAF mutation that can be further implied in the resistance phenomenon. Therefore, our data opens a new avenue for further studies in the short-term addressing novel targets that hopefully can be used to improve the therapeutic regiment in advanced melanoma patients. The innovating potential of this study is fully credible and has a real impact on the global patient society suffering from advanced and metastatic melanomas.